Disc therapy

ABSTRACT

Apparatus (20) for treating an intervertebral disc (30) of a subject is provided. The apparatus (20) includes at least three intra-pulposus exposed electrode surfaces (40), which are configured to be implanted within a nucleus pulposus (42) of the disc (30), at different respective locations; and one or more extra-pulposus exposed electrode surfaces (44), which are configured to be implanted outside the nucleus pulposus (42), in electrical communication with the disc (30). Control circuitry (50) is configured to (a) configure the intra-pulposus exposed electrode surfaces (40) to be cathodes, and the one or more extra-pulposus exposed electrode surfaces (44) to be one or more anodes, and (b) drive the intra-pulposus exposed electrode surfaces (40) and the one or more extra-pulposus exposed electrode surfaces (44) to electroosmotically drive fluid into the nucleus pulposus (40) to increase pressure in the disc (30).

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority from U.S. application Ser. No.14/982,187, filed Dec. 29, 2015, which is assigned to the assignee ofthe present application and is incorporated herein by reference.

FIELD OF THE APPLICATION

The present invention relates generally to therapeutic electricaltechniques, and specifically to apparatus and methods for application oftherapeutic electrical energy to the spinal column.

BACKGROUND OF THE APPLICATION

The intervertebral discs form cartilaginous joints between the endplates of vertebrae to provide shock absorption. The discs include twomain regions: the nucleus pulposus, which is an inner, soft and highlyhydrated structure, and the annulus fibrosus, which is a strongstructure including lamellae (concentric sheets of collagen fibers),which surrounds the nucleus. The three major constituents of the discsare water, fibrillar collagens, and aggrecan. The proportion of thesecomponents varies across the disc, with the nucleus having a higherconcentration of aggrecan and water and a lower collagen content thanother regions of the disc. The loss of water content, particularly inthe nucleus pulposus, is associated with disc degeneration, and with adecrease in disc height and abnormal loading of other spinal structures.

U.S. Pat. No. 8,577,469 to Gross, which is assigned to the assignee ofthe present application and is incorporated herein by reference,describes apparatus for treating an intervertebral disc of a subject.The apparatus includes a first electrode, configured to be inserted intoa nucleus pulposus of the disc, and a second electrode, configured to beplaced outside of the nucleus pulposus, in a vicinity of the nucleuspulposus. A control unit is configured to drive a current between thefirst and second electrodes, and to configure the current toelectroosmotically drive fluid between inside and outside the nucleuspulposus. Other embodiments are also described

US Patent Application Publication 2005/0277996 to Podhajsky describes amethod for reducing intervertebral pressure, including providing anelectrode, having proximal and distal ends, and a generator, which isoperatively connected to the proximal end of the electrode, and isconfigured to supply radiofrequency current thereto. The method alsoincludes inserting at least a portion of the distal end of the electrodeinto the nucleus pulposus of an intervertebral disc and activating thegenerator to heat the nucleus pulposus. The electrode may be insertedinto the intervertebral disc through its first lateral side and/or itssecond lateral side, and may be substantially parallel to the major orminor axis of the nucleus pulposus.

SUMMARY OF THE APPLICATION

In some applications of the present invention, a method of treating anintervertebral disc of comprises implanting, within a nucleus pulposusof the disc, at least three intra-pulposus exposed electrode surfaces atdifferent respective locations, and implanting one or moreextra-pulposus exposed electrode surfaces outside the nucleus pulposus,in electrical communication with the disc. Control circuitry isactivated to drive the intra-pulposus exposed electrode surfaces and theone or more extra-pulposus exposed electrode surfaces toelectroosmotically drive fluid between inside and outside the nucleuspulposus.

In some applications of the present invention, the control circuitry isactivated to increase pressure in the disc by electroosmotically drivingthe fluid into the nucleus pulposus. For some applications, the controlcircuitry is activated to configure the intra-pulposus exposed electrodesurfaces to be cathodes, and the one or more extra-pulposus exposedelectrode surfaces to be one or more anodes. For some applications, thecontrol circuitry is activated to configure the cathodes to be atdifferent respective negative potentials. For some applications, thecontrol circuitry is activated to set respective magnitudes of thenegative potentials at the cathodes, with respect to outside the nucleuspulposus, to be inversely related to respective distances between thegeometric center and the cathodes. In other words, the negativepotentials are greater closer to the geometric center. This approach isbased on the inventors' realization that the potential distributionwithin in a disc is not homogeneous, and in a pathological disc thenegative potential near the geometric center of the disc is reduced(i.e., closer to zero) as compared to a healthy disc. The application ofdiffering negative potentials at different locations within the disccorrects this abnormal negative potential distribution within thepathological disc.

In some applications of the present invention, a method comprisessystemically administering a drug to a blood circulation of a subject,and activating control circuitry to apply, using one or more implantedelectrodes, a current that drives the administered drug from the bloodcirculation into tissue of the subject, including at at least one pointin time at which the drug has a concentration in the blood circulationequal to at least 75% of a maximum concentration of the drug in theblood circulation.

There is therefore provided, in accordance with an inventive concept 1of the present invention, a method of treating an intervertebral disc ofa subject, including:

implanting, within a nucleus pulposus of the disc, at least threeintra-pulposus exposed electrode surfaces at different respectivelocations;

implanting one or more extra-pulposus exposed electrode surfaces outsidethe nucleus pulposus, in electrical communication with the disc; and

activating control circuitry to:

-   -   configure the intra-pulposus exposed electrode surfaces to be        cathodes, and the one or more extra-pulposus exposed electrode        surfaces to be one or more anodes, and    -   drive the intra-pulposus exposed electrode surfaces and the one        or more extra-pulposus exposed electrode surfaces to        electroosmotically drive fluid into the nucleus pulposus to        increase pressure in the disc.        Inventive concept 2. The method according to inventive concept        1, wherein implanting the intra-pulposus exposed electrode        surfaces includes implanting the intra-pulposus exposed        electrode surfaces such that if the intra-pulposus exposed        electrode surfaces were to be projected onto a transverse plane        of the disc, the intra-pulposus exposed electrode surfaces would        be at different respective projected locations in the transverse        plane.        Inventive concept 3. The method according to inventive concept        2, wherein implanting the intra-pulposus exposed electrode        surfaces includes implanting the intra-pulposus exposed        electrode surfaces such that if the intra-pulposus exposed        electrode surfaces were to be projected onto the transverse        plane of the disc, each of the intra-pulposus exposed electrode        surfaces would be at least 2 mm from a closest another one of        the intra-pulposus exposed electrode surfaces.        Inventive concept 4. The method according to inventive concept        2, wherein implanting the intra-pulposus exposed electrode        surfaces includes implanting the intra-pulposus exposed        electrode surfaces such that if the intra-pulposus exposed        electrode surfaces were to be projected onto the transverse        plane of the disc, at least two of the intra-pulposus exposed        electrode surfaces would be disposed at respective different        distances from a geometric center of the disc in the transverse        plane.        Inventive concept 5. The method according to inventive concept        4, wherein implanting the intra-pulposus exposed electrode        surfaces includes implanting the intra-pulposus exposed        electrode surfaces such that if the intra-pulposus exposed        electrode surfaces were to be projected onto the transverse        plane of the disc, at least three of the intra-pulposus exposed        electrode surfaces would be disposed at respective different        distances from the geometric center of the disc in the        transverse plane.        Inventive concept 6. The method according to inventive concept        4, wherein implanting the intra-pulposus exposed electrode        surfaces includes implanting the intra-pulposus exposed        electrode surfaces such that if the intra-pulposus exposed        electrode surfaces were to be projected onto the transverse        plane of the disc, at least one of the distances would be at        least 2 mm greater than another one of the distances.        Inventive concept 7. The method according to inventive concept        4, wherein implanting the intra-pulposus exposed electrode        surfaces includes implanting the intra-pulposus exposed        electrode surfaces such that if the intra-pulposus exposed        electrode surfaces were to be projected onto the transverse        plane of the disc, at least (a) a first one of the distances        would be at least 2 mm greater than a second one of the        distances, and (b) a third one of one of the distances would be        at least 2 mm greater than the second one of the distances.        Inventive concept 8. The method according to inventive concept        1, wherein implanting the intra-pulposus exposed electrode        surfaces includes implanting the intra-pulposus exposed        electrode surfaces such that if the intra-pulposus exposed        electrode surfaces were to be projected onto a transverse plane        of the disc, at least one of the intra-pulposus exposed        electrode surfaces would be disposed at a distance of no more        than 10 mm from a geometric center of the disc in the transverse        plane.        Inventive concept 9. The method according to inventive concept        1, wherein activating the control circuitry to drive the        intra-pulposus exposed electrode surfaces and the one or more        extra-pulposus exposed electrode surfaces to electroosmotically        drive the fluid into the nucleus pulposus includes activating        the control circuitry to apply:

(a) a first voltage between at least a first one of the intra-pulposusexposed electrode surfaces and at least one of the one or moreextra-pulposus exposed electrode surfaces, and

(b) a second voltage between at least a second one of the intra-pulposusexposed electrode surfaces and at least one of the one or moreextra-pulposus exposed electrode surfaces, the second voltage differentfrom the first voltage.

Inventive concept 10. The method according to inventive concept 9,wherein activating the control circuitry to drive the intra-pulposusexposed electrode surfaces and the one or more extra-pulposus exposedelectrode surfaces to electroosmotically drive the fluid into thenucleus pulposus includes activating the control circuitry to apply athird voltage between at least a third one of the intra-pulposus exposedelectrode surfaces and at least one of the one or more extra-pulposusexposed electrode surfaces, the third voltage different from at leastone of the first and the second voltages.Inventive concept 11. The method according to inventive concept 10,wherein the third voltage is different from both the first and thesecond voltages.Inventive concept 12. The method according to inventive concept 1,wherein implanting the at least three intra-pulposus exposed electrodesurfaces includes implanting, within the nucleus pulposus, at least fiveintra-pulposus exposed electrode surfaces at different respectivelocations.Inventive concept 13. The method according to inventive concept 12,wherein implanting the at least five intra-pulposus exposed electrodesurfaces includes implanting the at least five intra-pulposus exposedelectrode surfaces such that if the intra-pulposus exposed electrodesurfaces were to be projected onto a transverse plane of the disc, theintra-pulposus exposed electrode surfaces would be at differentrespective projected locations in the transverse plane.Inventive concept 14. The method according to inventive concept 1,wherein activating the control circuitry includes activating the controlcircuitry to configure the cathodes to be at different respectivenegative potentials.Inventive concept 15. The method according to inventive concept 14,

wherein if the cathodes were to be projected onto a transverse plane ofthe disc, one or more of the cathodes would be one or more respectiveclosest cathodes to a geometric center of the disc in the transverseplane of the disc, and

wherein activating the control circuitry includes activating the controlcircuitry to set respective magnitudes of the negative potentials at theone or more closest cathodes to be at least 30 mV with respect tooutside the nucleus pulposus.

Inventive concept 16. The method according to inventive concept 15,wherein activating the control circuitry includes activating the controlcircuitry to set the respective magnitudes of the negative potentials atthe one or more closest cathodes to be at least 40 mV with respect tooutside the nucleus pulposus.Inventive concept 17. The method according to inventive concept 15,

wherein if the cathodes were to be projected onto the transverse planeof the disc, one or more of the cathodes would be one or more respectivefarthest cathodes from the geometric center of the disc in thetransverse plane of the disc, and

wherein activating the control circuitry includes activating the controlcircuitry to set respective magnitudes of the negative potentials at theone or more farthest cathodes to be no more than 20 mV with respect tooutside the nucleus pulposus.

Inventive concept 18. The method according to inventive concept 14,

wherein implanting the intra-pulposus exposed electrode surfacesincludes implanting the intra-pulposus exposed electrode surfaces suchthat if the intra-pulposus exposed electrode surfaces were to beprojected onto a transverse plane of the disc, the intra-pulposusexposed electrode surfaces would be disposed at respective distancesfrom a geometric center of the disc in the transverse plane, and

wherein activating the control circuitry includes activating the controlcircuitry to set respective magnitudes of the negative potentials at thecathodes, with respect to outside the nucleus pulposus, to be inverselyrelated to the respective distances between the geometric center and thecathodes.

Inventive concept 19. The method according to inventive concept 18,

wherein if the cathodes were to be projected onto a transverse plane ofthe disc, one or more of the cathodes would be one or more respectiveclosest cathodes to a geometric center of the disc in the transverseplane of the disc, and one or more of the cathodes would be one or morerespective farthest cathodes to the geometric center of the disc in thetransverse plane of the disc, and

wherein activating the control circuitry includes activating the controlcircuitry to set respective magnitudes of the negative potentials at theone or more closest cathodes, with respect to outside the nucleuspulposus, to be greater than respective magnitudes of the negativepotential at the one or more farthest cathodes, with respect to outsidethe nucleus pulposus.

Inventive concept 20. The method according to inventive concept 19,wherein activating the control circuitry includes activating the controlcircuitry to set the respective magnitudes of the negative potentials atthe one or more closest cathodes, with respect to outside the nucleuspulposus, to be at least 20 mV greater than the respective magnitudes ofthe negative potentials at the one or more farthest cathodes, withrespect to outside the nucleus pulposus.Inventive concept 21. The method according to inventive concept 20,wherein activating the control circuitry includes activating the controlcircuitry to set the respective magnitudes of the negative potentials atthe one or more closest cathodes, with respect to outside the nucleuspulposus, to be at least 30 mV greater than the respective magnitudes ofthe negative potentials at the one or more farthest cathodes, withrespect to outside the nucleus pulposus.Inventive concept 22. The method according to inventive concept 1,wherein implanting the intra-pulposus exposed electrode surfacesincludes implanting the intra-pulposus exposed electrode surfacessymmetrically about a sagittal plane of the disc.Inventive concept 23. The method according to inventive concept 1,wherein implanting the intra-pulposus exposed electrode surfacesincludes implanting at least one intra-pulposus electrode, whichincludes:

at least two of the intra-pulposus exposed electrode surfaces; and

a support structure along which the at least two of the intra-pulposusexposed electrode surfaces are disposed, such that the support structureis shaped as a partial ring or a complete ring after the implanting.

Inventive concept 24. The method according to inventive concept 23,

wherein the disc defines a geometric center line segment perpendicularto a transverse plane of the disc, and

wherein implanting the at least one intra-pulposus electrode includesimplanting the at least one intra-pulposus electrode such that thesupport structure surrounds at least 180 degrees of the geometric centerline segment.

Inventive concept 25. The method according to inventive concept 24,wherein implanting the at least one intra-pulposus electrode includesimplanting the at least one intra-pulposus electrode such that thesupport structure surrounds at least 270 degrees of the geometric centerline segment.Inventive concept 26. The method according to inventive concept 23,wherein implanting the at least one intra-pulposus electrode includesimplanting the at least one intra-pulposus electrode such that thesupport structure is shaped as the complete ring that surrounds an areaof at least 1 cm2.Inventive concept 27. The method according to inventive concept 23,wherein implanting the at least one intra-pulposus electrode includesimplanting the at least one intra-pulposus electrode such that thesupport structure is shaped as the complete ring that surrounds an areaequal to at least 15% of a greatest area of the nucleus pulposusmeasured in a transverse plane of the disc.Inventive concept 28. The method according to inventive concept 23,wherein implanting the at least one intra-pulposus electrode includesimplanting the at least one intra-pulposus electrode such that thesupport structure is shaped as the partial ring that surrounds an areaof at least 1 cm2.Inventive concept 29. The method according to inventive concept 23,wherein implanting the at least one intra-pulposus electrode includesimplanting the at least one intra-pulposus electrode such that thesupport structure is shaped as the partial ring that surrounds an areaequal to at least 15% of a greatest area of the nucleus pulposusmeasured in a transverse plane of the disc.Inventive concept 30. The method according to inventive concept 23,wherein the at least one intra-pulposus electrode includes a partiallyinsulated wire, which serves as the support structure, and whereinnon-insulated portions of the wire serve as respective ones of theintra-pulposus exposed electrode surfaces.Inventive concept 31. The method according to inventive concept 1,wherein implanting the intra-pulposus exposed electrode surfacesincludes implanting at least one intra-pulposus electrode, whichincludes:

at least two of the intra-pulposus exposed electrode surfaces; and

a support structure along which the at least two of the intra-pulposusexposed electrode surfaces are disposed, such that the support structureremains straight during and after the implanting.

Inventive concept 32. The method according to inventive concept 31,wherein the at least one intra-pulposus electrode includes a partiallyinsulated wire, which serves as the support structure, and whereinnon-insulated portions of the wire serve as respective ones of theintra-pulposus exposed electrode surfaces.Inventive concept 33. The method according to inventive concept 31,

wherein the at least two of the intra-pulposus exposed electrodesurfaces include first, second, and third intra-pulposus exposedelectrode surfaces disposed along the support structure, with the secondlongitudinally between the first and the third intra-pulposus exposedelectrode surfaces, and

wherein activating the control circuitry includes activating the controlcircuitry to configure the first, the second, and the thirdintra-pulposus exposed electrode surfaces to be at respective differentpotentials, the potential at the second intra-pulposus exposed electrodesurface (a) greater than the potential at the first intra-pulposusexposed electrode surface, and (b) greater than the potential at thethird intra-pulposus exposed electrode surface.

Inventive concept 34. The method according to inventive concept 33,wherein implanting the intra-pulposus exposed electrode surfacesincludes implanting the intra-pulposus exposed electrode surfaces suchthat if the intra-pulposus exposed electrode surfaces were to beprojected onto a transverse plane of the disc:

the first, the second, and the third intra-pulposus exposed electrodesurfaces would be disposed at respective first, second, and thirddistances from a geometric center of the disc in the transverse plane,and

the second distance would be (a) less than the first distance, and (b)less than the third distance.

Inventive concept 35. The method according to inventive concept 1,wherein implanting the intra-pulposus exposed electrode surfacesincludes implanting at least one intra-pulposus electrode, whichincludes:

at least two of the intra-pulposus exposed electrode surfaces; and

a support structure, which includes a plurality of spines thatrespectively include one or more of the intra-pulposus exposed electrodesurfaces.

Inventive concept 36. The method according to inventive concept 35,wherein the support structure further includes a backbone, from whichthe spines extend.Inventive concept 37. The method according to inventive concept 35,wherein the support structure includes a partially insulated wire, andwherein non-insulated portions of the wire serve as respective ones ofthe intra-pulposus exposed electrode surfaces.Inventive concept 38. The method according to inventive concept 1,wherein implanting the one or more extra-pulposus exposed electrodesurfaces includes implanting the one or more extra-pulposus exposedelectrode surfaces within 1 mm of the nucleus pulposus of the disc.Inventive concept 39. The method according to inventive concept 1,wherein implanting the one or more extra-pulposus exposed electrodesurfaces includes implanting the one or more extra-pulposus exposedelectrode surfaces between 1 and 15 mm from the nucleus pulposus of thedisc.Inventive concept 40. The method according to inventive concept 1,wherein implanting the one or more extra-pulposus exposed electrodesurfaces includes implanting the one or more extra-pulposus exposedelectrode surfaces within 1 mm of an external surface of an annulusfibrosus of the disc.Inventive concept 41. The method according to inventive concept 1,wherein implanting the one or more extra-pulposus exposed electrodesurfaces includes implanting the one or more extra-pulposus exposedelectrode surfaces at least partially within an annulus fibrosus of thedisc.Inventive concept 42. The method according to inventive concept 1,wherein implanting the one or more extra-pulposus exposed electrodesurfaces includes implanting the one or more extra-pulposus exposedelectrode surfaces at an average distance from the nucleus pulposus ofthe disc that is inversely related to a number of the one or moreextra-pulposus exposed electrode surfaces being implanted.Inventive concept 43. The method according to inventive concept 1,wherein implanting the one or more extra-pulposus exposed electrodesurfaces includes implanting the one or more extra-pulposus exposedelectrode surfaces such that a product of (a) a number of the one ormore extra-pulposus exposed electrode surfaces times (b) an averagedistance in centimeters of the one or more extra-pulposus exposedelectrode surfaces from the nucleus pulposus equals between 4 and 15.Inventive concept 44. The method according to inventive concept 1,wherein activating the control circuitry includes activating the controlcircuitry to:

drive the intra-pulposus exposed electrode surfaces and the one or moreextra-pulposus exposed electrode surfaces to electroosmotically drivethe fluid into the nucleus pulposus during a plurality of discreteactivation periods alternating with non-activation periods, and

ramp a strength of currents applied between the intra-pulposus exposedelectrode surfaces and the one or more extra-pulposus exposed electrodesurfaces at a beginning of at least one of the activation periods suchthat the strength reaches a maximum value no earlier than 10 minutesafter the beginning of the period.

Inventive concept 45. The method according to inventive concept 44,wherein activating the control circuitry includes activating the controlcircuitry to set a length of at least one of the non-activation periodsto be at least 30 minutes.Inventive concept 46. The method according to inventive concept 1,wherein activating the control circuitry includes activating the controlcircuitry to drive the intra-pulposus exposed electrode surfaces and theone or more extra-pulposus exposed electrode surfaces toelectroosmotically drive the fluid into the nucleus pulposus based on acircadian cycle of the subject.Inventive concept 47. The method according to inventive concept 1,further including replacing the nucleus pulposus with an artificialsubstitute material before implanting the intra-pulposus exposedelectrode surfaces.

There is further provided, in accordance with an inventive concept 48 ofthe present invention, a method of treating an intervertebral disc of asubject, including:

implanting, within a nucleus pulposus of the disc, a support structurealong which one or more intra-pulposus exposed electrode surfaces aredisposed, such that the support structure is shaped as a partial ring ora complete ring after the implanting;

implanting one or more extra-pulposus exposed electrode surfaces outsidethe nucleus pulposus, in electrical communication with the disc; andactivating control circuitry to:

-   -   configure the intra-pulposus exposed electrode surfaces to be        cathodes, and the one or more extra-pulposus exposed electrode        surfaces to be one or more anodes, and,    -   drive the intra-pulposus exposed electrode surfaces and the one        or more extra-pulposus exposed electrode surfaces to        electroosmotically drive fluid into the nucleus pulposus to        increase pressure in the disc.        Inventive concept 49. The method according to inventive concept        48, wherein the support structure includes a wire, and wherein        the one or more intra-pulposus exposed electrode surfaces are        defined by one or more non-insulated portions of the wire.        Inventive concept 50. The method according to inventive concept        49, wherein the wire has a diameter of no more than 200 microns.        Inventive concept 51. The method according to inventive concept        48,

wherein the disc defines a geometric center line segment perpendicularto a transverse plane of the disc, and

wherein implanting the support structure includes implanting the supportstructure such that the support structure surrounds at least 180 degreesof the geometric center line segment.

Inventive concept 52. The method according to inventive concept 51,wherein implanting the support structure includes implanting the supportstructure such that the support structure surrounds at least 270 degreesof the geometric center line segment.Inventive concept 53. The method according to inventive concept 48,wherein implanting the support structure includes implanting the supportstructure such that the support structure is shaped as the complete ringthat surrounds an area of at least 1 cm2.Inventive concept 54. The method according to inventive concept 48,wherein implanting the support structure includes implanting the supportstructure such that the support structure is shaped as the complete ringthat surrounds an area equal to at least 15% of a greatest area of thenucleus pulposus measured in a transverse plane of the disc.Inventive concept 55. The method according to inventive concept 48,wherein implanting the support structure includes implanting the supportstructure such that the support structure is shaped as the partial ringthat surrounds an area of at least 1 cm2.Inventive concept 56. The method according to inventive concept 48,wherein implanting the support structure includes implanting the supportstructure such that the support structure is shaped as the partial ringthat surrounds an area equal to at least 15% of a greatest area of thenucleus pulposus measured in a transverse plane of the disc.

There is still further provided, in accordance with an inventive concept57 of the present invention, apparatus for treating an intervertebraldisc of a subject, the apparatus including:

at least three intra-pulposus exposed electrode surfaces, which areconfigured to be implanted within a nucleus pulposus of the disc, atdifferent respective locations;

one or more extra-pulposus exposed electrode surfaces, which areconfigured to be implanted outside the nucleus pulposus, in electricalcommunication with the disc; and

control circuitry, which is configured to:

-   -   configure the intra-pulposus exposed electrode surfaces to be        cathodes, and the one or more extra-pulposus exposed electrode        surfaces to be one or more anodes, and    -   drive the intra-pulposus exposed electrode surfaces and the one        or more extra-pulposus exposed electrode surfaces to        electroosmotically drive fluid into the nucleus pulposus to        increase pressure in the disc.        Inventive concept 58. The apparatus according to inventive        concept 57, wherein the apparatus includes at least five        intra-pulposus exposed electrode surfaces, which are configured        to be implanted implanting within the nucleus pulposus, at        different respective locations.        Inventive concept 59. The apparatus according to inventive        concept 57, wherein the control circuitry is configured to        configure the cathodes to be at different respective negative        potentials.        Inventive concept 60. The apparatus according to inventive        concept 57, wherein the control circuitry is configured to:

drive the intra-pulposus exposed electrode surfaces and the one or moreextra-pulposus exposed electrode surfaces to electroosmotically drivethe fluid into the nucleus pulposus during a plurality of discreteactivation periods alternating with non-activation periods, and

ramp a strength of currents applied between the intra-pulposus exposedelectrode surfaces and the one or more extra-pulposus exposed electrodesurfaces at a beginning of at least one of the activation periods suchthat the strength reaches a maximum value no earlier than 10 minutesafter the beginning of the period.

Inventive concept 61. The apparatus according to inventive concept 60,wherein the control circuitry is configured to set a length of at leastone of the non-activation periods to be at least 30 minutes.Inventive concept 62. The apparatus according to inventive concept 57,wherein the control circuitry is configured to drive the intra-pulposusexposed electrode surfaces and the one or more extra-pulposus exposedelectrode surfaces to electroosmotically drive the fluid into thenucleus pulposus based on a circadian cycle of the subject.Inventive concept 63. The apparatus according to any one of inventiveconcepts 57-62, wherein the control circuitry is configured to drive theintra-pulposus exposed electrode surfaces and the one or moreextra-pulposus exposed electrode surfaces to electroosmotically drivethe fluid into the nucleus pulposus by applying:

(a) a first voltage between at least a first one of the intra-pulposusexposed electrode surfaces and at least one of the one or moreextra-pulposus exposed electrode surfaces, and

(b) a second voltage between at least a second one of the intra-pulposusexposed electrode surfaces and at least one of the one or moreextra-pulposus exposed electrode surfaces, the second voltage differentfrom the first voltage.

Inventive concept 64. The apparatus according to inventive concept 63,wherein the control circuitry is configured to drive the intra-pulposusexposed electrode surfaces and the one or more extra-pulposus exposedelectrode surfaces to electroosmotically drive the fluid into thenucleus pulposus by applying a third voltage between at least a thirdone of the intra-pulposus exposed electrode surfaces and at least one ofthe one or more extra-pulposus exposed electrode surfaces, the thirdvoltage different from at least one of the first and the secondvoltages.Inventive concept 65. The apparatus according to inventive concept 64,wherein the third voltage is different from both the first and thesecond voltages.Inventive concept 66. The apparatus according to any one of inventiveconcepts 57-62, wherein the apparatus includes at least oneintra-pulposus electrode, which includes:

at least two of the intra-pulposus exposed electrode surfaces; and

a support structure along which the at least two of the intra-pulposusexposed electrode surfaces are disposed, wherein the support structureis configured to be shaped as a partial ring or a complete ring afterimplantation.

Inventive concept 67. The apparatus according to inventive concept 66,wherein the support structure is configured to be shaped as the completering that surrounds an area of at least 1 cm2.Inventive concept 68. The apparatus according to inventive concept 66,wherein the support structure is configured to be shaped as the partialring that surrounds an area of at least 1 cm2.Inventive concept 69. The apparatus according to inventive concept 66,wherein the at least one intra-pulposus electrode includes a partiallyinsulated wire, which serves as the support structure, and whereinnon-insulated portions of the wire serve as respective ones of theintra-pulposus exposed electrode surfaces.Inventive concept 70. The apparatus according to any one of inventiveconcepts 57-62, wherein the apparatus includes at least oneintra-pulposus electrode, which includes:

at least two of the intra-pulposus exposed electrode surfaces; and

a support structure along which the at least two of the intra-pulposusexposed electrode surfaces are disposed, wherein the support structureis configured to remain straight during and after implantation.

Inventive concept 71. The apparatus according to inventive concept 70,wherein the at least one intra-pulposus electrode includes a partiallyinsulated wire, which serves as the support structure, and whereinnon-insulated portions of the wire serve as respective ones of theintra-pulposus exposed electrode surfaces.Inventive concept 72. The apparatus according to inventive concept 70,

wherein the at least two of the intra-pulposus exposed electrodesurfaces include first, second, and third intra-pulposus exposedelectrode surfaces disposed along the support structure, with the secondlongitudinally between the first and the third intra-pulposus exposedelectrode surfaces, and

wherein the control circuitry is configured to configure the first, thesecond, and the third intra-pulposus exposed electrode surfaces to be atrespective different potentials, the potential at the secondintra-pulposus exposed electrode surface (a) greater than the potentialat the first intra-pulposus exposed electrode surface, and (b) greaterthan the potential at the third intra-pulposus exposed electrodesurface.

Inventive concept 73. The apparatus according to any one of inventiveconcepts 57-62, wherein the apparatus includes at least oneintra-pulposus electrode, which includes:

at least two of the intra-pulposus exposed electrode surfaces; and

a support structure, which includes a plurality of spines thatrespectively include one or more of the intra-pulposus exposed electrodesurfaces.

Inventive concept 74. The apparatus according to inventive concept 73,wherein the support structure further includes a backbone, from whichthe spines extend.Inventive concept 75. The apparatus according to inventive concept 73,wherein the support structure includes a partially insulated wire, andwherein non-insulated portions of the wire serve as respective ones ofthe intra-pulposus exposed electrode surfaces.

There is additionally provided, in accordance with an inventive concept76 of the present invention, apparatus for treating an intervertebraldisc of a subject, the apparatus including:

one or more intra-pulposus exposed electrode surfaces;

a support structure along which the one or more intra-pulposus exposedelectrode surfaces are disposed, wherein the support structure isconfigured to be implanted within a nucleus pulposus of the disc, and tobe shaped as a partial ring or a complete ring after implantation;

one or more extra-pulposus exposed electrode surfaces, which areconfigured to be implanted outside the nucleus pulposus, in electricalcommunication with the disc; and

control circuitry, which is configured to:

-   -   configure the intra-pulposus exposed electrode surfaces to be        cathodes, and the one or more extra-pulposus exposed electrode        surfaces to be one or more anodes, and    -   drive the intra-pulposus exposed electrode surfaces and the one        or more extra-pulposus exposed electrode surfaces to        electroosmotically drive fluid into the nucleus pulposus.        Inventive concept 77. The apparatus according to inventive        concept 76, wherein the support structure includes a wire, and        wherein the one or more intra-pulposus exposed electrode        surfaces are defined by one or more non-insulated portions of        the wire.        Inventive concept 78. The apparatus according to inventive        concept 77, wherein the wire has a diameter of no more than 200        microns.        Inventive concept 79. The apparatus according to inventive        concept 76, wherein the support structure is configured to be        shaped as the complete ring that surrounds an area of at least 1        cm2 upon implantation.        Inventive concept 80. The apparatus according to inventive        concept 76, wherein the support structure is configured to be        shaped as the partial ring that surrounds an area of at least 1        cm2 upon implantation.

There is yet additionally provided, in accordance with an inventiveconcept 81 of the present invention, a method including:

systemically administering a drug to a blood circulation of a subject;and

activating control circuitry to apply, using one or more implantedelectrodes, a current that drives the administered drug from the bloodcirculation into tissue of the subject, including at at least one pointin time at which the drug has a concentration in the blood circulationequal to at least 75% of a maximum concentration of the drug in theblood circulation.

Inventive concept 82. The method according to inventive concept 81,wherein driving the administered drug includes ceasing to drive theadministered drug within an amount of time after or before theconcentration drops below a percentage of the maximum concentration, theamount of time between 15 and 60 minutes, and the percentage between 5%and 20%.Inventive concept 83. The method according to inventive concept 81,wherein driving the administered drug includes ceasing to drive theadministered drug only after the concentration drops below 40% of themaximum concentration.Inventive concept 84. The method according to inventive concept 81,wherein driving includes beginning driving the administered drug within5 minutes before or after beginning systemically administering the drug.Inventive concept 85. The method according to inventive concept 84,wherein driving includes beginning driving the administered drug within1 minute before or after beginning systemically administering the drug.Inventive concept 86. The method according to inventive concept 81,wherein driving includes beginning driving the administered drug within5 minutes before or after beginning systemically administering the drug.Inventive concept 87. The method according to inventive concept 81,wherein driving includes beginning driving the administered drug withina certain amount of time before or after beginning systemicallyadministering the drug, the certain amount of time based onpredetermined pharmacokinetics of the drug.Inventive concept 88. The method according to inventive concept 81,wherein driving includes beginning driving the administered drug within5 minutes before or after the concentration of the drug in the bloodcirculation first exceeds 25% of the maximum concentration of the drugin the blood circulation.Inventive concept 89. The method according to inventive concept 81,wherein driving the drug includes providing a user-activation input tothe control circuitry, and wherein the control circuitry is configuredto begin driving the drug after a delay from receiving theuser-activation input.Inventive concept 90. The method according to inventive concept 89,wherein the delay is based on predetermined pharmacokinetics of thedrug.Inventive concept 91. The method according to inventive concept 81,wherein the one or more electrodes are implanted in the subject within 2cm of the tissue.Inventive concept 92. The method according to inventive concept 81,wherein the one or more electrodes are implanted in the subject within 1cm of the tissue.Inventive concept 93. The method according to inventive concept 81,wherein driving includes driving the administered drug for an amount oftime based on predetermined pharmacokinetics of the drug.Inventive concept 94. The method according to inventive concept 81,wherein driving the drug includes driving the drug from the bloodcirculation into an intervertebral disc of the subject.Inventive concept 95. The method according to inventive concept 81,wherein driving the drug includes driving the drug from the bloodcirculation into a kidney of the subject.Inventive concept 96. The method according to inventive concept 81,wherein driving the drug includes driving the drug from the bloodcirculation into cartilage of the subject.Inventive concept 97. The method according to inventive concept 81,wherein driving the drug includes driving the drug from the bloodcirculation into brain tissue of the subject.Inventive concept 98. The method according to inventive concept 97,wherein at least a first one of the electrodes is implanted in acerebral blood vessel, and at least a second one of the electrodes isimplanted in the brain tissue.Inventive concept 99. The method according to inventive concept 81,wherein systemically administering the drug includes parenterallyadministering the drug.Inventive concept 100. The method according to inventive concept 99,wherein systemically administering the drug includes injecting the drugto an intracorporeal site of the subject within 10 cm of the tissue.Inventive concept 101. The method according to inventive concept 81,wherein systemically administering the drug includes enterallyadministering the drug.Inventive concept 102. The method according to inventive concept 81,wherein systemically administering the drug includes implanting a drugreservoir containing the drug.Inventive concept 103. The method according to inventive concept 81,wherein systemically administering the drug includes transdermallyadministering the drug.Inventive concept 104. The method according to inventive concept 103,wherein transdermally administering the drug includes driving the drugthrough skin of the subject.Inventive concept 105. The method according to inventive concept 81,wherein systemically administering the drug includes systemicallyadministering the drug using an administration device that isconfigured, upon administering the drug, to activate the controlcircuitry to apply the current.Inventive concept 106. The method according to inventive concept 105,wherein the administration device includes a syringe, and whereinsystemically administering the drug includes systemically administeringthe drug using the syringe.

There is also provided, in accordance with an inventive concept 107 ofthe present invention, a method including:

administering a drug to a subject; and

driving the administered drug into target tissue of the subject, byactivating electrodes that were implanted in a body of the subject atleast one day before administering the drug, at least one of theelectrodes disposed within 2 cm of target tissue of the subject.

Inventive concept 108. The method according to inventive concept 107,wherein administering the drug includes administering the drug to anintracorporeal site of the subject within 10 cm of the target tissue.Inventive concept 109. The method according to inventive concept 107,wherein the at least one of the electrodes is disposed within 1 cm ofthe target tissue.

There is further provided, in accordance with an inventive concept 110of the present invention, a method including:

implanting electrodes in a body of a subject, such that at least one ofthe electrodes is disposed within 2 cm of target tissue of the subject;

implanting, in the body of the subject, control circuitry configured todrive the electrodes to apply an iontophoretic current configured todrive a drug into the target tissue; and

not implanting a drug reservoir containing the drug disposed fordelivery by the iontophoretic current.

Inventive concept 111. The method according to inventive concept 110,wherein implanting the electrodes includes implanting the electrodessuch that the at least one of the electrodes is disposed within 1 cm ofthe target tissue.

The present invention will be more fully understood from the followingdetailed description of embodiments thereof, taken together with thedrawings, in which:

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-C are schematic illustrations of a system for treating anintervertebral disc of a subject, in accordance with respectiveapplications of the present invention;

FIGS. 2A-C are schematic illustrations of additional configurations ofthe system of FIGS. 1A-C, in accordance with respective applications ofthe present invention; and

FIG. 3 is a schematic illustration of a method of administering a drug,in accordance with an application of the present invention.

DETAILED DESCRIPTION OF APPLICATIONS

FIGS. 1A-C are schematic illustrations of a system 20 for treating anintervertebral disc 30 of a subject, in accordance with respectiveapplications of the present invention. System 20 comprises (a) at leasttwo (typically, at least three) intra-pulposus exposed electrodesurfaces 40, which are electrically conductive, and which are configuredto be implanted (typically chronically) within a nucleus pulposus 42 ofdisc 30 at different respective locations, and (b) one or moreextra-pulposus exposed electrode surfaces 44, which are configured to beimplanted (typically chronically) outside nucleus pulposus 42, inelectrical communication with disc 30, in a vicinity of an externalsurface of an annulus fibrosus 46 of disc 30, e.g., in physical contactwith the external surface. Alternatively, second electrode 32 isconfigured to be at least partially inserted into annulus fibrosus 46(configuration not shown). System 20 further comprises implantable(typically chronically implantable) or external control circuitry 50,which is typically coupled to the exposed electrode surfaces by one ormore electrode leads 52. For some applications, control circuitry 50 isconfigured to control each of the exposed electrode surfaces separately;for example, control circuitry 50 may be electrically coupled to theexposed electrode surfaces separately via separate electricalconductors.

For some applications, the electrodes are implanted during aconventional surgical procedure to repair disc 30 and/or nucleuspulposus 42, including a standard approach for inserting a needle indisc 30.

For some applications, system 20 comprises at least one intra-pulposuselectrode, which comprises a support structure 54 which comprises or isshaped so as to define intra-pulposus exposed electrode surfaces 40. Forsome applications, support structure 54 comprises a shape memory alloy,such as Nitinol, which is configured to automatically assume apredetermined shape when in a relaxed state upon implantation in thedisc.

Reference is made to FIGS. 1B and 1C. For some applications, supportstructure 54 comprises a plurality of spines 56 that respectivelycomprise one or more (e.g., exactly one) of intra-pulposus exposedelectrode surfaces 40. For some applications, spines 56 assume theirrespective angular positions upon initial insertion through annulusfibrosus 46 and into nucleus pulposus 42, and then are advanced inrespective paths farther into nucleus pulposus 42. Alternatively, spines56 are advanced toward a geometric center 62 of disc 30 whileconstrained in an introducer tube (e.g., a hollow needle), and, uponrelease from the introducer tube, radially separate from one anotheruntil spines 56 assume their respective angular positions. For someapplications, such as shown in FIG. 1C, support structure 54 furthercomprises a backbone 58, from which spines 56 extend. For someapplications, the intra-pulposus electrode is implanted such thatbackbone 58 remains straight during and after the implanting.

For some applications, such as of the configurations shown in FIGS. 1Band 1C, support structure 54 comprises a partially insulated wire, andnon-insulated portions of the wire serve as respective ones ofintra-pulposus exposed electrode surfaces 40. For some applications, thewire has a diameter of at least 10 microns, such as at least 20 microns,and no more than 200 microns, such as no more than 100 microns, no morethan 50 microns, or no more than 10 microns. Such a fine electrodegenerally avoids any potential damage to the disc. For someapplications, the electrode is introduced within an introducer, whichmay, for example, have an outer diameter of between 100 and 300 microns,e.g., between 100 and 200 microns.

For some applications, intra-pulposus exposed electrode surfaces 40 areshaped to have a relatively large surface area. For example,intra-pulposus exposed electrode surfaces 40 may be shaped as bladesrather than cylinders. Large surface areas allow application of greatercurrent at any given voltage. In general, in these applications it isdesired for the voltage to not exceed 1.2 V, in order to minimize therisk of causing electrolysis of at least one of the electrode surfaces.

In some applications of the present invention, a method of treatingintervertebral disc 30 comprises implanting, within nucleus pulposus 42of disc 30, the at least two (typically at least three, e.g., at leastfour, at least five, at least six, at least seven, or more than seven)intra-pulposus exposed electrode surfaces 40 at different respectivelocations. The method further comprises implanting the one or moreextra-pulposus exposed electrode surfaces 44 outside nucleus pulposus42, in electrical communication with disc 30.

After the intra-pulposus exposed electrode surfaces 40 and the one ormore extra-pulposus exposed electrode surfaces 44 have been implanted,control circuitry 50 is activated to drive the intra-pulposus exposedelectrode surfaces 40 and the one or more extra-pulposus exposedelectrode surfaces 44 to electroosmotically drive fluid between insideand outside nucleus pulposus 42.

Typically, a healthcare worker, such as a physician, activates controlcircuitry 50 to provide the functions described herein. Activating thecontrol circuitry may include configuring parameters and/or functions ofthe control circuitry (such as using a separate programmer or externalcontroller), or activating the control circuitry to perform functionspre-programmed in the control circuitry. Control circuitry 50 typicallycomprises appropriate memory, processor(s), and hardware runningsoftware that is configured to provide the functionality of the controlcircuitry described herein.

For some applications, the intra-pulposus exposed electrode surfaces 40are implanted such that if intra-pulposus exposed electrode surfaces 40were to be projected onto a transverse plane 60 of disc 30, theintra-pulposus exposed electrode surfaces 40 would be at differentrespective projected locations 61 in transverse plane 60. It is notedthat intra-pulposus exposed electrode surfaces 40 may be implanted atdifferent respective heights within disc 30 (i.e., axial positions alongthe vertebral column), i.e., intra-pulposus exposed electrode surfaces40 may or may not be implanted in transverse plane 60. The projection ofintra-pulposus exposed electrode surfaces 40 onto transverse plane 60described and claimed in the present application is not a physical stepof the implantation method, but is instead a geometric way of describingthe relative positions of the electrode surfaces.

For some applications, intra-pulposus exposed electrode surfaces 40 areimplanted such that if intra-pulposus exposed electrode surfaces 40 wereto be projected onto transverse plane 60, each of intra-pulposus exposedelectrode surfaces 40 would be at least 2 mm from a closest another oneof the intra-pulposus exposed electrode surfaces 40, such as at least 3mm, e.g., at least 5 mm, as measured between closest respective pointsof the two intra-pulposus exposed electrode surfaces 40. For example, inthe blow-ups in FIGS. 1A and 1B, a first intra-pulposus exposedelectrode surface 40A is at a distance D1 from a closest secondintra-pulposus exposed electrode surface 40B.

For some applications, intra-pulposus exposed electrode surfaces 40 areimplanted such that if intra-pulposus exposed electrode surfaces 40 wereto be projected onto transverse plane 60, at least two of intra-pulposusexposed electrode surfaces 40 would be disposed at respective differentdistances from geometric center 62 of disc 30 in transverse plane 60, asmeasured between closest respective points of the at least two ofintra-pulposus exposed electrode surfaces 40 and geometric center 62.For example, in the blow-up in FIGS. 1A and 1B, first intra-pulposusexposed electrode surface 40A is at a distance D2 from geometric center62, and second intra-pulposus exposed electrode surface 40B is at adistance D3 from geometric center 62.

For some applications, intra-pulposus exposed electrode surfaces 40 areimplanted such that if intra-pulposus exposed electrode surfaces 40 wereto be projected onto transverse plane 60, at least three ofintra-pulposus exposed electrode surfaces 40 would be disposed atrespective different distances from geometric center 62 of disc 30 intransverse plane 60, as measured between closest respective points ofthe at least three of intra-pulposus exposed electrode surfaces 40 andgeometric center 62. Alternatively or additionally, for someapplications, intra-pulposus exposed electrode surfaces 40 are implantedsuch that if intra-pulposus exposed electrode surfaces 40 were to beprojected onto transverse plane 60, at least one of the distances wouldbe at least 2 mm greater than another one of the distances, such as atleast 3 mm greater, e.g., at least 5 mm greater.

Further alternatively or additionally, for some applications,intra-pulposus exposed electrode surfaces 40 are implanted such that ifintra-pulposus exposed electrode surfaces 40 were to be projected ontotransverse plane 60, at least (a) a first one of the distances fromgeometric center 62 would be at least 2 mm greater than a second one ofthe distances from geometric center 62 (e.g., at least 3 mm greater,such as at least 5 mm greater), and (b) a third one of one of thedistances from geometric center 62 would be at least 2 mm greater thanthe second one of the distances from geometric center 62 (e.g., at least3 mm greater, such as at least 5 mm greater).

Alternatively or additionally, for some applications, the intra-pulposusexposed electrode surfaces 40 are implanted such that a smallest one ofthe distances from geometric center 62 is no more than 5 mm, such as nomore than 3 mm, e.g., no more than 2 mm, such as no more than 1 mm.Still further alternatively or additionally, for some applications,intra-pulposus exposed electrode surfaces 40 are implanted such that ifintra-pulposus exposed electrode surfaces 40 were to be projected ontotransverse plane 60, at least one of intra-pulposus exposed electrodesurfaces 40 would be disposed at a distance of no more than 10 mm, suchas no more than 5 mm, from a geometric center of disc 30 in transverseplane 60, as measured between a closest point of the intra-pulposusexposed electrode surface 40 and geometric center 62.

As used in the present application, including in the claims, geometriccenter 62 (also known in the mathematical arts as the centroid) is thearithmetic mean (“average”) position of all the points in disc 30(including both nucleus pulposus 42 and annulus fibrosus 46). As used inthe present application, including in the claims, a transverse plane(also called the horizontal plane, axial plane, or transaxial plane) isan imaginary plane that divides the body into superior and inferiorparts, and is perpendicular to the coronal and sagittal planes.

For some applications, as shown in FIGS. 1A and 1B, intra-pulposusexposed electrode surfaces 40 are implanted symmetrically about asagittal plane 80 of disc 30 (i.e., with reflection symmetry).

For some applications, control circuitry 50 is configured to driveintra-pulposus exposed electrode surfaces 40 and the one or moreextra-pulposus exposed electrode surfaces 44 to electroosmotically drivefluid between inside and outside nucleus pulposus 42 by applying (a) afirst voltage between at least a first one of intra-pulposus exposedelectrode surfaces 40 and at least one of the one or more extra-pulposusexposed electrode surfaces 44, and (b) a second voltage between at leasta second one of intra-pulposus exposed electrode surfaces 40 and atleast one of the one or more extra-pulposus exposed electrode surfaces44, the second voltage different from the first voltage. For some ofthese applications, control circuitry 50 is configured to driveintra-pulposus exposed electrode surfaces 40 and the one or moreextra-pulposus exposed electrode surfaces 44 to electroosmotically drivefluid between inside and outside nucleus pulposus 42 by applying a thirdvoltage between at least a third one of intra-pulposus exposed electrodesurfaces 40 and at least one of the one or more extra-pulposus exposedelectrode surfaces 44, the third voltage different from at least one ofthe first and the second voltages, such as different from both the firstand the second voltages. For example, control circuitry 50 may beconfigured to separately drive respective currents betweenintra-pulposus exposed electrode surfaces 40 and the one or moreextra-pulposus exposed electrode surface 44.

For some applications, control circuitry 50 is activated to configurethe current to increase pressure in disc 30 by electroosmoticallydriving the fluid into nucleus pulposus 42. Such an increase in fluid innucleus pulposus 42 generally treats or prevents further degeneration ofthe disc caused at least in part by loss of fluid. Typically, in theseapplications, control circuitry 50 is activated to configure theintra-pulposus exposed electrode surfaces 40 to be cathodes, and the oneor more extra-pulposus exposed electrode surface 44 to be one or moreanodes. The applied current may also help introduce nutritionalsubstances into the disc.

For some of these applications, control circuitry 50 is configured toconfigure the cathodes to be at different respective negative potentials(typically, by separately controlling each of the cathodes). For some ofthese applications, if the cathodes were to be projected onto transverseplane 60, one or more of the cathodes would be one or more respectiveclosest cathodes 70 to geometric center 62 of disc 30 in transverseplane 60, as measured between closest respective points of the cathodesand geometric center 62 of disc 30. Control circuitry 50 is configuredto set respective magnitudes of the negative potentials at the one ormore closest cathodes 70 to be at least 30 mV with respect to outsidenucleus pulposus 42, such as at least 40 mV with respect to outsidenucleus pulposus 42. Alternatively or additionally, for some of theseapplications, if the cathodes were to be projected onto transverse plane60, one or more of the cathodes would be one or more respective farthestcathodes 72 from geometric center 62 of disc 30 in transverse plane 60,and control circuitry 50 is configured to set respective magnitudes ofthe negative potentials at the one or more farthest cathodes 72 to be nomore than 20 mV with respect to outside nucleus pulposus 42.

For some applications, control circuitry 50 is configured to setrespective magnitudes of the negative potentials at the cathodes, withrespect to outside nucleus pulposus 42, to be inversely related torespective distances between geometric center 62 and the cathodes. Forsome of these applications, if the cathodes were to be projected ontotransverse plane 60, one or more of the cathodes would be one or morerespective closest cathodes 70 to geometric center 62 of disc 30 intransverse plane 60, and one or more of the cathodes would be one ormore respective farthest cathodes 72 to geometric center 62 of disc 30in transverse plane 60. Control circuitry 50 is configured to setrespective magnitudes of the negative potentials at the one or moreclosest cathodes 70, with respect to outside nucleus pulposus 42, to begreater than respective magnitudes of the negative potential at the oneor more farthest cathodes 72, with respect to outside nucleus pulposus42. For some applications, control circuitry 50 is configured to set therespective magnitudes of the negative potentials at the one or moreclosest cathodes 70, with respect to outside nucleus pulposus 42, to beat least 20 mV greater than (e.g., at least 30 mV greater than) therespective magnitudes of the negative potentials at the one or morefarthest cathodes 72, with respect to outside nucleus pulposus 42,and/or to be no more than 1.2 V (e.g., no more than 70 mV) greater thanthe respective magnitudes of the negative potentials at the one or morefarthest cathodes 72, with respect to outside nucleus pulposus 42.

For some applications, intra-pulposus exposed electrode surfaces 40 areconfigured to apply respective currents, such that at least two of thecurrents are different from each other, even though the same voltage isapplied. For example, intra-pulposus exposed electrode surfaces 40 maybe coated with slightly-insulating coatings, with at least two of thecoatings having differing thicknesses. Alternatively, at least two ofintra-pulposus exposed electrode surfaces 40 may have different lengthsor surface areas.

For some applications, control circuitry 50 is activated to configurethe current to reduce pressure in disc 30 by electroosmotically drivingthe fluid from nucleus pulposus 42, such as in order to treat discherniation. For an example, one or more intra-pulposus exposed electrodesurfaces 40 may be positioned close to the zone of the herniation, andone or more extra-pulposus exposed electrode surfaces 44 may bepositioned immediately outside the herniation. For example, an electrodemount (e.g., shaped like a two-headed rivet) may be provided that isshaped so as to cross annulus fibrosus 46 and hold the intra-pulposusand extra-pulposus exposed electrode surfaces 40 and 42 in place.Typically, in these applications, control circuitry 50 is activated toconfigure intra-pulposus exposed electrode surfaces 40 to be anodes, andthe one or more extra-pulposus exposed electrode surfaces 44 to be oneor more cathodes. These applications may implement any of the techniquesand parameters described herein for applications in which intra-pulposusexposed electrode surfaces 40 are configured to be cathodes, with thereverse polarity.

For some applications, control circuitry 50 is activated to apply avoltage of up to 1.2 V, for example, between 200 and 500 mV, betweenintra-pulposus exposed electrode surfaces 40 and the one or moreextra-pulposus exposed electrode surface 44. (Typically, the naturalvoltage across the outer membrane of disc 30 is about 50-70 mV.) Forsome applications, control circuitry 50 is activated to apply thecurrent with a low frequency, such as between 0.5 and 2 Hz. Thisfrequency is typically insufficient to stimulate a nerve, whichtypically requires about 5-20 Hz. Alternatively or additionally, theduty cycle is typically low, e.g., less than 40%. Typically, controlcircuitry 50 is activated to apply the current monophasically, in orderto drive the fluid in only one direction. In contrast, nerve stimulatorstypically apply a few volts, and do not cause electrolysis because theapplied signal is biphasic.

Reference is now made to FIGS. 2A-C, which are schematic illustrationsof additional configurations of system 20, in accordance with respectiveapplications of the present invention. In the configurations shown inFIGS. 2A-B, implanting intra-pulposus exposed electrode surfaces 40comprises implanting at least one intra-pulposus electrode 100, whichcomprises (a) at least two of intra-pulposus exposed electrode surfaces40, and (b) a support structure 106 along which the at least two ofintra-pulposus exposed electrode surfaces 40 are disposed, such thatsupport structure 106 is shaped as a partial ring 108 (as shown in FIG.2A) or a complete ring 110 (as shown in FIG. 2B) after the implanting.For some applications, support structure 106 comprises a shape memoryalloy, such as Nitinol, which is configured to automatically assume thepartial or complete ring shape when in a relaxed state upon implantationin the disc. For some applications, the intra-pulposus electrode 100 isimplanted from the angular approach shown in FIG. 2C.

Disc 30 defines a geometric center line segment 120 perpendicular totransverse plane 60 of disc 30. For some applications, the at least oneintra-pulposus electrode 100 is implanted such that support structure106 surrounds at least 180 degrees of geometric center line segment 120,such as at least 210 degrees, at least 240 degrees, at least 270degrees, at least 300 degrees, at least 330 degrees, or 360 degrees (asshown in FIG. 2B).

For some applications, such as shown in FIG. 2A, the at least oneintra-pulposus electrode 100 is implanted such that the supportstructure is shaped as partial ring 108 that surrounds an area of atleast 1 cm2, such as at least 1.5 cm2 or at least 2 cm2 and/or an areaequal to at least 15%, such as at least 20% or at least 25%, of agreatest area of nucleus pulposus 42 measured in a transverse plane ofdisc 30. For some applications, partial ring 108 has a length, measuredalong support structure 106, of at least 1.5 cm (e.g., at least 2 cm),no more than 6 cm (e.g., no more than 4 cm), and/or between 1.5 cm(e.g., 2 cm) and 6 cm (e.g., 4 cm).

For some applications, such as shown in FIG. 2B, the at least oneintra-pulposus electrode 100 is implanted such that support structure106 is shaped as complete ring 110 that surrounds an area of at least 1cm2, such at least 1.5 cm2 or at least 2 cm2 and/or an area equal to atleast 15%, such as at least 20% or at least 25%, of a greatest area ofnucleus pulposus 42 measured in a transverse plane of disc 30. For someapplications, complete ring 110 has a perimeter of at least 1.5 cm(e.g., at least 2 cm), no more than 6 cm (e.g., no more than 4 cm),and/or between 1.5 cm (e.g., 2 cm) and 6 cm (e.g., 4 cm).

For some applications, such as of the configurations shown in FIGS. 2Aand 2B, support structure 106 is shaped and intra-pulposus exposedelectrode surfaces 40 are disposed on support structure 106 such that,upon implantation, intra-pulposus exposed electrode surfaces 40 areapproximately equidistant from geometric center line segment 120, i.e.,(a) a first distance between center line segment 120 and a first one ofthe intra-pulposus exposed electrode surfaces 40 farthest from centerline segment 120 is no more than 120%, e.g., 110%, of (a) a seconddistance between center line segment 120 and a second one of theintra-pulposus exposed electrode surfaces 40 closest to center linesegment 120.

For some applications, such as of the configurations shown in FIGS. 2Aand 2B, the at least one intra-pulposus electrode 100 comprises apartially insulated wire, which serves as support structure 106, andnon-insulated portions of the wire serve as respective ones ofintra-pulposus exposed electrode surfaces 40. For some applications, thewire has a diameter of at least 10 microns, such as at least 20 microns,and no more than 200 microns, such as no more than 100 microns, no morethan 50 microns, or no more than 10 microns. Such a fine electrodegenerally avoids any potential damage to the disc. For someapplications, the electrode is introduced within an introducer, whichmay, for example, have an outer diameter of between 100 and 300 microns,e.g., between 100 and 200 microns.

For some applications, the configurations shown in FIGS. 2A and 2B areinstead implemented using a single, long intra-pulposus exposedelectrode surface 40. For some applications, the single intra-pulposusexposed electrode surface 40 has a perimeter of at least 1.5 cm (e.g.,at least 2 cm), no more than 6 cm (e.g., no more than 4 cm), and/orbetween 1.5 cm (e.g., 2 cm) and 6 cm (e.g., 4 cm).

In the configuration shown in FIG. 2C, implanting intra-pulposus exposedelectrode surfaces 40 comprises implanting at least one intra-pulposuselectrode 200, which comprises: (a) at least two of intra-pulposusexposed electrode surfaces 40, and (b) a support structure 222 alongwhich the at least two of intra-pulposus exposed electrode surfaces 40are disposed, such that support structure 222 remains straight duringand after the implanting. For some applications, intra-pulposus exposedelectrode surfaces 40 are implanted such that if intra-pulposus exposedelectrode surfaces 40 were to be projected onto transverse plane 60, aclosest one of intra-pulposus exposed electrode surfaces 40 would bedisposed within 10 mm, such as 5 mm, of geometric center 62 of disc 30in transverse plane 60, as measured between a closest point of theintra-pulposus exposed electrode surface and geometric center 62. Forsome applications, support structure 222 comprises a shape memory alloy,such as Nitinol.

For some applications, the at least two of intra-pulposus exposedelectrode surfaces 40 include first, second, and third intra-pulposusexposed electrode surfaces 40A, 40B, and 40C disposed along supportstructure 222, with second intra-pulposus exposed electrode surface 40Blongitudinally between first and third intra-pulposus exposed electrodesurfaces 40A and 40C. Control circuitry 50 is activated to configurefirst, second, and third intra-pulposus exposed electrode surfaces 40A,40B, and 40C to be at respective negative potentials (e.g., negativepotentials), the potential (e.g., negative potential) at secondintra-pulposus exposed electrode surface 40B (a) greater than thepotential (e.g., negative potential) at first intra-pulposus exposedelectrode surface 40A, and (b) greater than the potential (e.g.,negative potential) at third intra-pulposus exposed electrode surface40C. For some applications, the potential (e.g., negative potential) atfirst intra-pulposus exposed electrode surface 40A is equal to thepotential (e.g., negative potential) at third intra-pulposus exposedelectrode surface 40C.

For some applications, intra-pulposus exposed electrode surfaces 40 areimplanted such that if intra-pulposus exposed electrode surfaces 40 wereto be projected onto transverse plane 60: (a) first, second, and thirdintra-pulposus exposed electrode surfaces 40A, 40B, and 40C would bedisposed at respective first, second, and third distances from geometriccenter 62 in transverse plane 60, as measured between closest respectivepoints of the intra-pulposus exposed electrode surfaces and geometriccenter 62, and (b) the second distance would be (a) less than the firstdistance, and (b) less than the third distance. For some applications,the first distance equals the second distance.

Although intra-pulposus electrode 200 is shown in FIG. 2C as comprisingthree intra-pulposus exposed electrode surfaces 40, intra-pulposuselectrode 200 may alternatively comprise more intra-pulposus exposedelectrode surfaces 40, such as 4, 5, 6, 7, 8, or 9 intra-pulposusexposed electrode surfaces 40. For example, intra-pulposus electrode 200may comprise 7 intra-pulposus exposed electrode surfaces 40, and controlcircuitry 50 may be activated to configure the negative potentials atintra-pulposus exposed electrode surfaces 40 to be −30 mV, −40 mV, −45mV, −50 mV, −45 mV, −40 mV, and −30 mV, respectively, with respect tooutside the nucleus pulposus.

Reference is made to FIGS. 1A-2C. For some applications, the one or moreextra-pulposus exposed electrode surfaces 44 are implanted within 1 mmof nucleus pulposus 42 of disc 30, or between 1 and 15 mm, such asbetween 1 and 5 mm, from nucleus pulposus 42 of disc 30. For someapplications, the one or more extra-pulposus exposed electrode surfaces44 are implanted within 1 mm of the external surface of annulus fibrosus46, such as in contact with the external surface. Alternatively oradditionally, for some applications, the one or more extra-pulposusexposed electrode surfaces 44 are implanted at least partially withinannulus fibrosus 46 of disc 30.

For some applications, the more extra-pulposus exposed electrodesurfaces 44 provided, the closer the extra-pulposus exposed electrodesurfaces are implanted to nucleus pulposus 42, in order to generate agenerally uniform flow of current from the electrode surfaces within thedisc to outside of the disc. If instead only a single extra-pulposusexposed electrode surface 44 were provided and it were positioned nearor touching the disc, a distorted field distribution would result.However, if the single extra-pulposus exposed electrode surface 44 isdisposed farther from the disc, a more uniform field results becausecurrent flows somewhat equally between the single extra-pulposus exposedelectrode surface 44 and each of the intra-pulposus exposed electrodesurfaces 40. Nevertheless, the inventors have identified that it wouldbe desirable not to place extra-pulposus exposed electrode surface 44 sofar from the disc that the voltage required to maintain a sufficientcurrent would exceed about 1.2 V, because this would have a risk ofcausing electrolysis of at least one of the electrode surfaces.Correspondingly, if more intra-pulposus exposed electrode surfaces 40are provided, they may be disposed closer to the disc and still resultin a generally uniform field distribution. For some applications, inlight of the above considerations, two to four (e.g., three)extra-pulposus exposed electrode surfaces 44 are used, and are disposedwithin 2, 3, or 4 cm of the disc, but greater than 1 cm from the disc.

For some applications, the one or more extra-pulposus exposed electrodesurfaces 44 are implanted at an average distance from nucleus pulposus42 that is inversely related to a number of the one or moreextra-pulposus exposed electrode surfaces 44 being implanted. Forexample, the one or more extra-pulposus exposed electrode surfaces 44may be implanted such that a product of (a) the number of the one ormore extra-pulposus exposed electrode surfaces 44 times (b) the averagedistance in centimeters of the one or more extra-pulposus exposedelectrode surfaces 44 from the nucleus pulposus equals between 4 and 15.

For some applications, control circuitry 50 is configured to applydirect current, e.g., with an average amplitude of between 1 and 5 mA.For some applications, the control unit is configured to apply thedirect current with an average amplitude of less than 1.2 V. For someapplications, the control unit is configured to apply the direct currentas a series of pulses. For some applications, the control unit isconfigured to apply the direct current as the series of pulses with aduty cycle of between 1% and 50%.

Reference is still made to FIGS. 1A-2C. For some applications, controlcircuitry 50 is configured to:

-   -   drive intra-pulposus exposed electrode surfaces 40 and the one        or more extra-pulposus exposed electrode surfaces 44 to        electroosmotically drive fluid between inside and outside        nucleus pulposus 42 during a plurality of discrete activation        periods alternating with non-activation periods, and    -   ramp a strength of currents applied between intra-pulposus        exposed electrode surfaces 40 and the one or more extra-pulposus        exposed electrode surfaces 44 at a beginning of at least one of        the activation periods such that the strength reaches a maximum        value no earlier than 10 minutes after the beginning of the        period, such as no earlier than 15 minutes after the beginning        of the period.        Such a slow ramp-up in the strength may simulate natural        physiology, rather provide a step function. For some        applications, control circuitry 50 is configured to set a length        of at least one of the non-activation periods to be at least 30        minutes.

For some applications, control circuitry 50 is configured to driveintra-pulposus exposed electrode surfaces 40 and the one or moreextra-pulposus exposed electrode surfaces 44 to electroosmotically drivefluid between inside and outside nucleus pulposus 42 based on acircadian cycle of the subject.

Reference is still made to FIGS. 1A-2C. For some applications, a housingcontaining control circuitry is injectable, with an anchor at theproximal end. One or more extra-pulposus exposed electrode surfaces 44are fixed to an external surface of the housing. For example, thehousing may be implanted immediately posterior to the spinal column.

Reference is still made to FIGS. 1A-2C. For some applications, controlcircuitry 50 is configured to be implanted subcutaneously, if thehousing containing the control circuitry is small. Alternatively, forsome applications, control circuitry 50 is configured to be implanted orelsewhere in the subject's body, if the housing of the control circuitryis larger (e.g., includes batteries).

For some applications, control circuitry 50 is driven by an externalcontroller that is in wireless or wired communication with controlcircuitry 50. For some applications, the external controller is mountedon a bed of the subject (e.g., disposed within a mattress), and isconfigured to activate control circuitry 50 only at night, and/or onlywhen the subject is sleeping. Such nighttime activation may coincidewith and support the filling phase of the disc, and thus be therapeuticeven though the patient experiences more pain during the day.Alternatively or additionally, control circuitry 50 is activated duringthe daytime, i.e., over the course of the day, because the pressure ishigher in the disc during application of vertical and mechanical load onthe disc, which causes the disc to lose fluid; the activation may thisreduce maximum damage to the disc. Further alternatively, the controlcircuitry is activated generally constantly, or regularly intermittently(e.g., one hour on/one hour off). For some applications, controlcircuitry 50 is activated during rest of the subject, rather than duringactivity; for example, an accelerometer may be provided to identifymovement vs. rest of the subject.

For some applications, control circuitry 50 is configured to provide thesubject with control of activation of control circuitry 50, e.g., inresponse to activity or pain. For example, the control may be providedfrom the subject's telephone (e.g., smartphone) or other electronicdevice.

For some applications, the method further comprises replacing nucleuspulposus 42 with an artificial substitute material before implantingintra-pulposus exposed electrode surfaces 40.

A first experiment was conducted on behalf of the inventors to study thefeasibility of using some of the techniques described hereinabove withreference to FIGS. 1A-2C to hydrate and dehydrate a spinal disc, and theimpact of the voltage application on the disc mass. The experimentevaluated three electrical protocols: (a) negative voltage inside thenucleus pulposus of the disc vs. outside the disc, (b) positive voltageinside the nucleus pulposus of the disc vs. outside the disc, and (c)control (no voltage applied to the nucleus pulposus of the disc). It wasfound that application of a negative voltage inside the nucleus pulposusof the disc enhanced the hydration of the disc, as compared to apositive voltage or no voltage. No dehydration effect was observed withapplication of a positive voltage to the nucleus pulposus.

The experiment used a total of six fresh bovine tail discs. In order toachieve equilibrium, the discs were placed in a saline solution for aperiod of one hour prior to application of the voltages. The discs werethen weighed. The discs were randomly assigned to the experimentalgroups as follows: (a) two specimens—negative voltage inside the nucleuspulposus of the disc vs. outside the disc, (b) two specimens—positivevoltage inside the nucleus pulposus of the disc vs. outside the disc,and (c) two specimens—control (no voltage applied to the nucleuspulposus of the disc).

The discs were placed inside a vessel and fully submerged in salinesolution. One electrode was inserted in the approximate center of thenucleus pulposus of each of the discs in experimental groups (a) and(b). The electrode was electrically-insulated except at its tip, and wasdesigned to allow submersion in liquid. The electrode was insertedlaterally (i.e., through the annulus of the disc). A second, ringelectrode was placed within the saline solution surrounding the disc.

Voltages of (a) −1 V and (b) +1 V were applied between the electrodes inthe two experimental groups (a) and (b), respectively. These voltageswere selected to be lower than the electrolysis voltage of water ofabout 1.2 V. After a period of two hours, the discs were removed andweighed again.

As set forth in Table 1 below, all of the discs increased in mass duringthe voltage-application period. The mass of the discs to which thenegative internal voltage was applied increased by 4.7% and 5.5%, whilethe mass of the other discs (positive internal voltage and control)increased by between 2.0% and 2.6%.

The inventors hypothesize that all of the discs absorbed liquid, whilethe application of the negative internal voltage contributed to anadditional absorption of 2-3%. The application of the positive internalvoltage did not result in dehydration of the disc.

TABLE 1 Mass after 2 Mass after 1 hours voltage Mass Mass Disc hourimmersion Voltage application change change # [g] (internal) [g] [g] [%]1 3.342 −1 V 3.527 0.185 5.5% 2 4.384 −1 V 4.590 0.206 4.7% 3 6.552 +1 V6.720 0.168 2.6% 4 4.558 +1 V 4.651 0.093 2.0% 5 7.346 0 7.531 0.1852.5% 6 6.074 0 6.209 0.135 2.2%

A second experiment was conducted on behalf of the inventors to studythe feasibility of using some of the techniques described hereinabovewith reference to FIGS. 1A-2C to hydrate a spinal disc and the impact ofthe voltage application on the disc mass. The experiment evaluated twoelectrical protocols: (a) negative voltage inside the nucleus pulposusof the disc vs. outside the disc, and (b) control (no voltage applied tothe nucleus pulposus of the disc). It was found that application of anegative voltage inside the nucleus pulposus of the disc enhanced thehydration of the disc, as compared to no voltage. Higher voltagemarkedly increased the mass gain.

The experiment used a total of six fresh bovine tail discs. The discswere randomly assigned to the experimental groups as follows: (a) threespecimens—negative voltage inside the nucleus pulposus of the disc vs.outside the disc, and (b) three specimens—control (no voltage applied tothe nucleus pulposus of the disc).

The discs were weighed, and then placed inside a vessel and fullysubmerged in saline solution. One electrode was inserted in theapproximate center of the nucleus pulposus of each of the discs in theexperimental group (a). The electrode was electrically-insulated exceptat its tip, and was designed to allow submersion in liquid. Theelectrode was inserted laterally (i.e., through the annulus of thedisc). A second, ring electrode was placed within the saline solutionsurrounding the disc.

A voltage of −1 V was applied between the electrodes in the experimentalgroup (a). One hour after the beginning of application of the voltage, afirst pair of two of the discs (one negative voltage, one control) wereremoved and weighed. In the two remaining negative voltage discs, thevoltage was increased to −3 V.

Two hours after the beginning of application of the voltage, a secondpair of two of the discs (one negative voltage, one control) wereremoved and weighed.

Three hours after the beginning of application of the voltage, a thirdpair of two of the discs (one negative voltage, one control) wereremoved and weighed.

As set forth in Table 2 below, all of the discs increased in mass duringthe voltage-application period. In each pair, the disc to which thevoltage was applied increased in mass more than the control disc did.Increasing the voltage from −1 V to −3 V resulted in a markedlyincreased mass gain. It was noted, however, that the −3 V voltageapplication resulted in electrolysis of the solution, which was expectedsince the electrolysis threshold of water is about 1.2 V. Thiselectrolysis was observed as bubbles and discoloration in the solution.

The inventors hypothesize that all of the discs absorbed liquid, whilethe application of the negative internal voltage contributed to anadditional absorption.

TABLE 2 Duration of Ending Mass Disc Starting mass Voltage voltage masschange # [g] (internal) application [g] [%] 1 6.047 −1 V 1 hour 6.3454.93% 2 6.227 0 1 hour 6.420 3.10% 3 5.988 −1 V, −3 V 2 hours 6.60510.30% 4 5.192 0 2 hours 5.444 4.85% 5 4.484 −1 V, −3 V 3 hours 5.26217.35% 6 4.236 0 3 hours 4.619 9.04%

The inventors hypothesize that application of −3 V, although possiblynot suitable for clinical use, served as a proxy for the effectivenessof longer-term voltage application at a lower voltage, such as −1 V.

As mentioned above, the discs were placed in a saline-dye solutionduring the experiment. The dye was methylene blue. After weighing thediscs, the discs were also dissected and inspected for dye penetration.In general, dye penetration was not observed in the discs.

Reference is now made to FIG. 3, which is a schematic illustration of amethod of administering a drug, in accordance with an application of thepresent invention. The method comprises systemically administering thedrug to a blood circulation of a subject 300, and activating controlcircuitry 310 to apply, using one or more implanted electrodes 320, acurrent that drives the administered drug from the blood circulationinto tissue of subject 300, including at at least one point in time atwhich the drug has a concentration in the blood circulation equal to atleast 75% of a maximum concentration of the drug in the bloodcirculation. For example, the current may drive the drug into the tissueiontophoretically and/or electroosmotically (e.g., fluid may be driveninto the tissue electroosmotically, and the drug may be driven into thetissue iontophoretically). The drug typically is water-soluble, and hasan effective polarity and/or net electric charge once dissolved inwater. For some applications, control circuitry 310 and/or implantedelectrodes 320 are implemented using techniques described hereinabovewith reference to FIGS. 1A-C, 2A, 2B, and/or 2C, mutatis mutandis.

As used in the present application, including in the claims, systemicadministration means the administration of a drug into the circulatorysystem so that the entire body is affected, and may occur via enteraladministration or parenteral administration (e.g., injection, infusion,or implantation).

For some applications, driving the administered drug comprises ceasingto drive the administered drug within an amount of time after or beforethe concentration drops below a percentage of the maximum concentration,the amount of time between 15 and 60 minutes, and the percentage between5% and 20%.

For some applications, driving the administered drug comprises ceasingto drive the administered drug only after the concentration drops below40% of the maximum concentration.

For some applications, driving comprises beginning driving theadministered drug within 5 minutes before or after beginningsystemically administering the drug. For some applications, drivingcomprises beginning driving the administered drug within 1 minute beforeor after beginning systemically administering the drug., such as within5 seconds before or after beginning systemically administering the drug,e.g., simultaneously with beginning systemically administering the drug.

For some applications, driving comprises beginning driving theadministered drug within 5 minutes before or after beginningsystemically administering the drug.

For some applications, driving comprises beginning driving theadministered drug within a certain amount of time before or afterbeginning systemically administering the drug, the certain amount oftime based on predetermined pharmacokinetics of the drug. For someapplications, driving comprises driving the administered drug for anamount of time based on predetermined pharmacokinetics of the drug. Forexample, the predetermined pharmacokinetics of the drug may bedetermined based on studies (pharmacokenetics), rather than personallyfor the subject; alternatively, the predetermined pharmacokinetics ofthe drug may be determined personally for the patient, such as using asensor.

For some applications, driving comprises beginning driving theadministered drug within 5 minutes before or after the concentration ofthe drug in the blood circulation first exceeds 25% of the maximumconcentration of the drug in the blood circulation.

For some applications, driving the drug comprises providing auser-activation input to control circuitry 310, and control circuitry310 is configured to begin driving the drug after a delay from receivingthe user-activation input. For some applications, the delay is based onpredetermined pharmacokinetics of the drug.

For some applications, the one or more electrodes 320 are implanted inthe subject within 2 cm of the tissue, such 1 cm of the tissue, e.g.,with 0.5 cm of the tissue.

For some applications, driving the drug comprises driving the drug fromthe blood circulation into intervertebral disc 30 of the subject (asshown in FIG. 3), a kidney of the subject, an eye of the subject, orcartilage of the subject, such as cartilage of the knee.

For other applications, driving the drug comprises driving the drug fromthe blood circulation into brain tissue of the subject (across theblood-brain barrier). For example, at least a first one of electrodes320 may be implanted in a cerebral blood vessel (e.g., a vein), and atleast a second one of electrodes 320 may be implanted in the braintissue); for example, control circuitry 310 may configure the first oneof electrodes 320 to have a negative potential, and the second one ofelectrodes 320 to have a positive potential. For example, the drug maybe administered to treat Alzheimer's disease.

More generally, the drug may be driven across any membrane in the body.

For some applications, systemically administering the drug comprisesparenterally administering the drug, such as by injection or infusion.For some applications, systemically administering the drug comprisesinjecting the drug to an intracorporeal site of the subject within 10 cmof the tissue (i.e., the administration apparatus (e.g., needle) ispositioned at the intracorporeal site, not that the drug eventuallyarrives at the intracorporeal site). For other applications,systemically administering the drug comprises enterally (e.g., orally orsublingually) administering the drug. Alternatively, systemicallyadministering the drug comprises implanting a drug reservoir containingthe drug. Alternatively, systemically administering the drug comprisestransdermally administering the drug, such as by driving the drugthrough skin of the subject.

For some applications, the drug is systemically administered using anadministration device that is configured, upon administering the drug,to activate control circuitry 310 to apply the current. For someapplications, the administration device comprises a syringe, andsystemically administering the drug comprises systemically administeringthe drug using the syringe.

Reference is still made to FIG. 3. In some applications of the presentinvention, a method is provided that comprises administering a drug tosubject 300, and driving the administered drug into target tissue of thesubject, by activating electrodes 320 that were implanted in a body ofthe subject at least one day before administering the drug, at least oneof the electrodes disposed within 2 cm of target tissue of the subject.

For some applications, administering the drug comprises administeringthe drug to an intracorporeal site of the subject within 2 cm of thetarget tissue. For some applications, the at least one of the electrodesis disposed within 1 cm of the target tissue, such as within 0.5 cm ofthe target tissue.

Reference is still made to FIG. 3. In some applications of the presentinvention, a method is provided that comprises:

-   -   implanting electrodes 320 in a body of subject 300, such that at        least one of electrodes 320 is disposed within 2 cm of target        tissue of the subject;    -   implanting, in the body of subject 300, control circuitry 310        configured to drive electrodes 320 to apply an iontophoretic        current configured to drive a drug into the target tissue; and    -   not implanting a drug reservoir containing the drug disposed for        delivery by the iontophoretic current.

For some applications, implanting electrodes 320 comprises implantingelectrodes 320 such that the at least one of the electrodes 320 isdisposed within 1 cm of the target tissue, such as within 0.5 cm of thetarget tissue.

In some applications of the present invention, the techniques andapparatus described herein are combined with techniques and apparatusdescribed in one or more of the following applications, which areassigned to the assignee of the present application and are incorporatedherein by reference:

-   -   U.S. Pat. No. 8,577,469 to Gross; and    -   US Patent Application Publication 2014/0324128 to Gross.

It will be appreciated by persons skilled in the art that the presentinvention is not limited to what has been particularly shown anddescribed hereinabove. Rather, the scope of the present inventionincludes both combinations and subcombinations of the various featuresdescribed hereinabove, as well as variations and modifications thereofthat are not in the prior art, which would occur to persons skilled inthe art upon reading the foregoing description.

1. Apparatus for treating an intervertebral disc of a subject, theapparatus comprising: at least three intra-pulposus exposed electrodesurfaces, which are configured to be implanted within a nucleus pulposusof the disc, at different respective locations; one or moreextra-pulposus exposed electrode surfaces, which are configured to beimplanted outside the nucleus pulposus, in electrical communication withthe disc; and control circuitry, which is configured to: configure theintra-pulposus exposed electrode surfaces to be cathodes at differentrespective negative potentials, and the one or more extra-pulposusexposed electrode surfaces to be one or more anodes, and drive theintra-pulposus exposed electrode surfaces and the one or moreextra-pulposus exposed electrode surfaces to electroosmotically drivefluid into the nucleus pulposus to increase pressure in the disc.
 2. Theapparatus according to claim 1, wherein the apparatus comprises at leastfive intra-pulposus exposed electrode surfaces, which are configured tobe implanted implanting within the nucleus pulposus, at differentrespective locations.
 3. The apparatus according to claim 6, wherein thecontrol circuitry is configured to configure the cathodes to be atdifferent respective negative potentials.
 4. The apparatus according toclaim 1, wherein the control circuitry is configured to: drive theintra-pulposus exposed electrode surfaces and the one or moreextra-pulposus exposed electrode surfaces to electroosmotically drivethe fluid into the nucleus pulposus during a plurality of discreteactivation periods alternating with non-activation periods, and ramp astrength of currents applied between the intra-pulposus exposedelectrode surfaces and the one or more extra-pulposus exposed electrodesurfaces at a beginning of at least one of the activation periods suchthat the strength reaches a maximum value no earlier than 10 minutesafter the beginning of the period.
 5. The apparatus according to claim4, wherein the control circuitry is configured to set a length of atleast one of the non-activation periods to be at least 30 minutes. 6.Apparatus for treating an intervertebral disc of a subject, theapparatus comprising: at least three intra-pulposus exposed electrodesurfaces, which are configured to be implanted within a nucleus pulposusof the disc, at different respective locations; one or moreextra-pulposus exposed electrode surfaces, which are configured to beimplanted outside the nucleus pulposus, in electrical communication withthe disc; and control circuitry, which is configured to: configure theintra-pulposus exposed electrode surfaces to be cathodes, and the one ormore extra-pulposus exposed electrode surfaces to be one or more anodes,and drive the intra-pulposus exposed electrode surfaces and the one ormore extra-pulposus exposed electrode surfaces to electroosmoticallydrive fluid into the nucleus pulposus to increase pressure in the discbased on a circadian cycle of the subject.
 7. Apparatus for treating anintervertebral disc of a subject, the apparatus comprising: at leastthree intra-pulposus exposed electrode surfaces, which are configured tobe implanted within a nucleus pulposus of the disc, at differentrespective locations; one or more extra-pulposus exposed electrodesurfaces, which are configured to be implanted outside the nucleuspulposus, in electrical communication with the disc; and controlcircuitry, which is configured to: configure the intra-pulposus exposedelectrode surfaces to be cathodes, and the one or more extra-pulposusexposed electrode surfaces to be one or more anodes, and drive theintra-pulposus exposed electrode surfaces and the one or moreextra-pulposus exposed electrode surfaces to electroosmotically drivefluid into the nucleus pulposus to increase pressure in the disc byapplying: (a) a first voltage between at least a first one of theintra-pulposus exposed electrode surfaces and at least one of the one ormore extra-pulposus exposed electrode surfaces, and (b) a second voltagebetween at least a second one of the intra-pulposus exposed electrodesurfaces and at least one of the one or more extra-pulposus exposedelectrode surfaces, the second voltage different from the first voltage.8. The apparatus according to claim 7, wherein the control circuitry isconfigured to drive the intra-pulposus exposed electrode surfaces andthe one or more extra-pulposus exposed electrode surfaces toelectroosmotically drive the fluid into the nucleus pulposus by applyinga third voltage between at least a third one of the intra-pulposusexposed electrode surfaces and at least one of the one or moreextra-pulposus exposed electrode surfaces, the third voltage differentfrom at least one of the first and the second voltages.
 9. The apparatusaccording to claim 8, wherein the third voltage is different from boththe first and the second voltages.
 10. The apparatus according to claim1, wherein the apparatus comprises at least one intra-pulposuselectrode, which comprises: at least two of the intra-pulposus exposedelectrode surfaces; and a support structure along which the at least twoof the intra-pulposus exposed electrode surfaces are disposed, whereinthe support structure is configured to be shaped as a partial ring or acomplete ring after implantation.
 11. The apparatus according to claim10, wherein the support structure is configured to be shaped as thecomplete ring that surrounds an area of at least 1 cm2.
 12. Theapparatus according to claim 10, wherein the support structure isconfigured to be shaped as the partial ring that surrounds an area of atleast 1 cm2.
 13. The apparatus according to claim 10, wherein the atleast one intra-pulposus electrode comprises a partially insulated wire,which serves as the support structure, and wherein non-insulatedportions of the wire serve as respective ones of the intra-pulposusexposed electrode surfaces.
 14. The apparatus according to claim 1,wherein the apparatus comprises at least one intra-pulposus electrode,which comprises: at least two of the intra-pulposus exposed electrodesurfaces; and a support structure along which the at least two of theintra-pulposus exposed electrode surfaces are disposed, wherein thesupport structure is configured to remain straight during and afterimplantation.
 15. The apparatus according to claim 14, wherein the atleast one intra-pulposus electrode comprises a partially insulated wire,which serves as the support structure, and wherein non-insulatedportions of the wire serve as respective ones of the intra-pulposusexposed electrode surfaces.
 16. The apparatus according to claim 14,wherein the at least two of the intra-pulposus exposed electrodesurfaces comprise first, second, and third intra-pulposus exposedelectrode surfaces disposed along the support structure, with the secondlongitudinally between the first and the third intra-pulposus exposedelectrode surfaces, and wherein the control circuitry is configured toconfigure the first, the second, and the third intra-pulposus exposedelectrode surfaces to be at the respective different negativepotentials, the negative potential at the second intra-pulposus exposedelectrode surface (a) greater than the negative potential at the firstintra-pulposus exposed electrode surface, and (b) greater than thenegative potential at the third intra-pulposus exposed electrodesurface.
 17. The apparatus according to claim 1, wherein the apparatuscomprises at least one intra-pulposus electrode, which comprises: atleast two of the intra-pulposus exposed electrode surfaces; and asupport structure, which comprises a plurality of spines thatrespectively comprise one or more of the intra-pulposus exposedelectrode surfaces.
 18. The apparatus according to claim 17, wherein thesupport structure further comprises a backbone, from which the spinesextend.
 19. The apparatus according to claim 17, wherein the supportstructure comprises a partially insulated wire, and whereinnon-insulated portions of the wire serve as respective ones of theintra-pulposus exposed electrode surfaces. 20-24. (canceled)